The human forebrain is the organ responsible for many of our uniquely human qualities, including reasoning, emotion and memory. This complex organ can be afflicted by a wide array of diseases from developmental abnormalities with lifelong consequences to later onset diseases such as neurodegeneration, or tumorigenesis. Despite this importance, there is much to learn about the molecular control of brain development. One approach to gain further understanding of the brain is to uncover more of the genetic components involved in its development, function and disease. The mouse, especially with its unique genetic tools, serves as an excellent model for human physiology and recent advances in genomic technologies allow us to apply large scale genetic approaches to studies of the brain. This proposal will use mouse genetic tools in a mutagenesis experiment to identify and begin to characterize novel genes required for normal development and function of the mouse brain. ENU mutagenesis in the mouse is an established tool to create autosomal recessive mutations, similar to those found in the human population, which can then be mapped and cloned. The aims of the proposal are to (1) screen for ENU- induced mutations in the mouse which affect brain development, and (2) begin to characterize two of the mutations already identified in preliminary studies. The identification of new alleles required for brain development is likely to contribute to our current state of understanding of the brain's development and function. Recent advances in our understanding of human disease have demonstrated the significant connection between individual genetic makeup and causation of, or predisposition to, specific diseases. One way to further study the roots of human disease is the use of similar experimental animal models to discover new genes related to specific disorders. By identifying more of the underlying causes of disease, the function of these genes can be elucidated, leading to increased treatments for the ultimate treatment and resolution of human disorders. This proposal is designed to uncover some of the fundamental mechanisms in brain development and disease.